Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor.
Erlotinib is described chemically as N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine, and its hydrochloride salt is represented by the compound of Formula I.

Erlotinib is disclosed in EP0817775 which also a discloses process for its preparation, which involves adding 3-ethynylaniline and 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline in isopropanol containing pyridine and then refluxing the mixture for 4 hours under the atmosphere of dry nitrogen. The solvent is removed and residue is extracted in 10% methanol in CHCl3 and saturated aqueous NaHCO3. N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine base is separated chromatographically and converted to the hydrochloride salt in a solvent such as CHCl3 using hydrochloric acid.
EP1044969 claims a method for preparing intermediates and compounds covering erlotinib. This patent discloses a process for preparing N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine which involves stirring 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol with anhydrous sodium hydroxide and 2-methoxyethanol and heating at reflux for 47 hours. The reaction mixture is cooled to 20-25° C. and concentrated HCl is added to it. The resulting mixture is granulated at 20-25° C. to crystallize the product.
Indian patent application 902/CHE/2006 discloses a process for preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The process involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy) benzaldehyde. This 3,4-bis(2-methoxyethoxy) benzaldehyde is converted to 3,4-bis(2-methoxyethoxy) benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy) benzonitrile. The benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile which is further reduced to obtain 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile. N′-(3-ethynylphenyl)-N,N-dimethyl formamidine obtained on formylation of 3-ethynylaniline with N,N-dimethyl formamidine is coupled with 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile to obtain erlotinib free base which on treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.
Indian patent application 904/CHE/2006 also discloses a process for preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The process involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy) benzaldehyde. This 3,4-bis(2-methoxyethoxy) benzaldehyde is converted to 3,4-bis(2-methoxyethoxy) benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy) benzonitrile. The benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile which is further reduced to get 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile. 2-amino-4,5-bis(2-methoxyethoxy) benzonitrile is formylated with a formylating agent in the presence of formic acid derivative to obtain N′-[2-cyano-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine which is coupled with an aniline derivative to obtain erlotinib free base which on treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.
The processes described in the prior art require anhydrous conditions and are carried out under an inert atmosphere. These processes are time consuming and cumbersome. Also a large variety of solvents are required for extraction and purification. Hence, there is a need for the development of a simple and industrially economical process.